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J Biol Chem. 2017 Jul 21;292(29):12025-12040. doi: 10.1074/jbc.M117.775981. Epub 2017 May 22.

Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site.

Author information

1
From the Department of Medicine, University of Utah Health Sciences Center School of Medicine, Salt Lake City, Utah 84132-2408.
2
Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112-5650.
3
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas 75080.
4
Department of Biochemistry and.
5
X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, Texas 78229.
6
Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, and.
7
Institute of Environmental Health, Oregon Health and Science University, Portland, Oregon 97239.
8
Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, University of Texas Health Science Center, San Antonio, Texas 78229.
9
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas 75080, duane.winkler@utdallas.edu.

Abstract

Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed "entry site" for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond-requiring enzyme in the cytoplasm, and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.

KEYWORDS:

X-ray crystallography; chaperone; copper; enzyme activation; metalloenzyme; superoxide dismutase (SOD)

PMID:
28533431
PMCID:
PMC5519355
DOI:
10.1074/jbc.M117.775981
[Indexed for MEDLINE]
Free PMC Article

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